Cyclohexyl acid pyrazole azines as LPA antagonists
The present invention provides compounds of Formula (I): or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein all the variables are as defined herein. These compounds are selective LPA receptor inhibitors.
1. A compound according to Formula (I):
or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof, wherein
X 1 , X 2 , X 3 , and X 4 are each independently CR 6 or N; provided that no more than two of X 1 , X 2 , X 3 , or X 4 are N;
Q 2 is N or NR 5b ;
one of Q 1 and Q 3 is CR 5a , and the other is N or NR 5b ;
the dashed circle denotes optional bonds forming an aromatic ring;
L is a covalent bond or C 1-4 alkylene substituted with 0 to 4 R 7 ;
Z is NR 8 or O;
the Y ring is phenyl or an azine moiety;
R 1 is (—CH 2 ) a R 9 ;
a is an integer of 0 or 1;
R 2 is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy;
n is an integer of 0, 1, or 2;
R 3 is halo, cyano, hydroxyl, amino, oxo, —OR a , —SR a , ═S, —NR c R c , ═NH, ═N—OH, ═NR a , ═N—OR a , —NO 2 , —S(O) 2 R a , —S(O) 2 NHR b , —S(O) 2 NR c R c , —S(O) 2 OR b , —OS(O) 2 R b , —OS(O) 2 OR b , —P(O)(OR b )(OR b ), —C(O)R b , —C(NR b )R b , —C(O)OR b , —C(O)NR c R c , —C(NR b )NR c R c , —OC(O)R b , —NR b C(O)R b , —OC(O)OR b , —NR b C(O)OR b , —OC(O)NR c R c , —NR b C(O)NR c R c , —NR b C(NR b )R b , —NR b C(NR b )NR c R c , C 1-6 alkyl, C 1-6 deuterated alkyl, C 1-6 heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and R a , by themselves or as part of another group, are each independently substituted with 0 to 5 R d ;
R a is selected from the group consisting of C 1-6 alkyl, C 1-6 deuterated alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;
R b is each independently hydrogen or R a ;
R c is each independently R b ; or alternatively, two R c , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl;
R d is each independently selected from the group consisting of R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR a , —SR a , ═S, —NR c R c , ═NH, ═N—OH, ═NR a , ═N—OR a , —NO 2 , —S(O) 2 R a , —S(O) 2 NHR b , —S(O) 2 NR c R c , —S(O) 2 OR b , —OS(O) 2 R b , —OS(O) 2 OR b , —P(O)(OR b )(OR b ), —C(O)R b , —C(NR b )R b , —C(O)OR b , —C(O)NR c R c , —C(NR b )NR c R c , —OC(O)R b , —NR b C(O)R b , —OC(O)OR b , —NR b C(O)OR b , —NR b C(O)NR c R c , —NR b C(NR b )R b , and —NR b C(NR b )NR c R c ; or alternatively one or two R d on alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, taken together with the atoms to which the R d is attached, form a cyclic or bridge moiety;
R 4 is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy; or R 3 and R 4 , taken together with the atoms to which they are attached, form a monocyclic or bicyclic ring moiety;
m is an integer of 0, 1, or 2;
R 5a and R 6 are each independently hydrogen, halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 5b is hydrogen, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 7 is halo, oxo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
R 8 is hydrogen or C 1-4 alkyl;
R 9 is selected from the group consisting of —CN, —C(O)OR 10 , —C(O)NR 11a R 11b ,
R e is C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or haloalkoxyalkyl;
R 10 is hydrogen or C 1-10 alkyl; and
R 11a and R 11b are each independently hydrogen, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy.
2. The compound according to claim 1 , wherein the
moiety is
and
Y 1 , Y 2 , Y 3 , and Y 4 are each independently N or CH with the proviso that at least one of Y 1 , Y 2 , Y 3 , and Y 4 is CH.
3. The compound according to claim 2 , wherein the
moiety is
4. The compound according to claim 3 , wherein
R 3 is halo, cyano, hydroxyl, amino, —OR a , —SR a , —NR c R c , C 1-6 alkyl, C 1-6 heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl; wherein the alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and R a , by themselves or as part of another group, are each independently substituted with 0 to 5 R d ,
R a is selected from the group consisting of C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;
R b is each independently hydrogen or R a ;
R c is each independently R b ; or alternatively, two R c , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl; and
R d is each independently selected from the group consisting of R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR a , —SR a , and —NR c R c ; or alternatively one or two R d on alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, taken together with the atoms to which the R d is attached, form a cyclic or bridge moiety.
5. The compound according to claim 1 , which is represented by Formula (IIa) or (IIb):
Y 1 , Y 2 , and Y 3 are each independently N or CH;
R 7a is hydrogen, halo, oxo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy;
f is an integer of 0, 1, 2, or 3; and
R 5a and R 5b are independently hydrogen or C 1-4 alkyl.
6. The compound according to claim 5 , wherein X 1 is CR 6 , where R 6 is hydrogen or C 1-4 alkyl.
7. The compound according to claim 6 , wherein X 3 is N.
8. The compound according to claim 7 , wherein the
moiety is selected from
R 6a is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, alkoxy, or haloalkoxy; and
d is an integer of 0, 1, or 2.
9. The compound according to claim 8 , wherein f is 0 or 1.
10. The compound according to claim 9 , wherein R 8 is hydrogen or methyl.
11. The compound according to claim 10 , wherein R 1 is CO 2 H.
12. The compound according to claim 1 , which is represented by Formula (IIa) or (IIb):
Y 1 , Y 2 , and Y 3 are each independently N or CH;
Z is O or NH; and
R 2a is hydrogen, chloro, fluoro, or C 1-4 alkyl.
13. The compound according to claim 12 , wherein the
moiety is selected from
14. The compound according to claim 13 , wherein R 1 is CO 2 H.
15. The compound according to claim 14 , wherein
X 1 is CR 5 ;
X 2 is N or CH;
X 3 is N; and
X 4 is N or CH; and
R 5 is hydrogen, halo, cyano, C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, or alkoxy.
16. The compound according to claim 15 , wherein the
moiety is
and R 6a is hydrogen, methyl, or ethyl.
17. The compound according to claim 16 , wherein the
moiety is
and m is 0 or 1.
18. The compound according to claim 17 , wherein the
moiety is
and m is 0 or 1.
19. The compound according to claim 18 , whrein
R 3 is halo, cyano, hydroxyl, amino, —OR a , —SR a , —NR c R c , C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 1-6 heteroalkyl, 6- to 10-membered aryl, arylalkyl, 5- to 10-membered heteroaryl, heteroarylalkyl, 3- to 8-membered carbocyclyl, carbocyclylalkyl, 4- to 8-membered heterocyclyl, or heterocyclylalkyl; wherein the alkyl, alkoxy, haloalkyl, haloalkoxy, heteroalkyl, aryl, heteroaryl, carbocyclyl, heterocyclyl, and R a , by themselves or as part of another group, are each independently substituted with 0 to 5 R d ,
R a is selected from the group consisting of C 1-6 alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxyalkyl, haloalkoxyalkyl, aryl, arylalkyl, heteroaryl, heteroarylalkyl, carbocyclyl, carbocyclylalkyl, heterocyclyl, and heterocyclylalkyl;
R b is each independently hydrogen or R a ;
R c is each independently R b ; or alternatively, two R c , taken together with the nitrogen atom to which they are attached, form a 4- to 7-membered heterocyclyl;
R d is each independently selected from the group consisting of R a , alkoxy, haloalkoxy, alkylamino, cycloalkylamino, heterocyclylamino, haloalkyl, hydroxyalkyl, aminoalkyl, cycloalkoxy, heterocyclyloxy, haloalkoxy, alkoxyalkoxy, haloalkylamino, alkoxyalkylamino, haloalkoxyalkylamino, arylamino, aralkylamino, aryloxy, aralkyloxy, heteroaryloxy, heteroarylalkyloxy, alkylthio, halo, cyano, hydroxyl, amino, oxo, —OR a , —SR a , and —NR c R c ; or alternatively one or two R d on alkyl, heteroalkyl, aryl, heteroaryl, carbocyclyl, or heterocyclyl, taken together with the atoms to which the R d is attached, form a cyclic or bridge moiety,
m is 0, 1, or 2; and
R 4 is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, C 4-6 heterocyclyl, alkylamino, haloalkyl, hydroxyalkyl, aminoalkyl, alkoxy, alkoxyalkyl, haloalkoxyalkyl, or haloalkoxy.
20. The compound according to claim 19 , wherein
R 3 is C 1-6 alkyl, C 1-6 alkoxy, C 1-6 haloalkyl, C 1-6 haloalkoxy, C 3-6 cycloalkyl, phenyl, benzyl, (a 6-membered heteroaryl containing 1 to 3 heteroatoms each of which is independently selected from N, O, and S), alkoxy, alkoxyalkyl, —O—cycloalkyl, —O—phenyl, —O—benzyl, and —NH-alkyl; and each of the alkyl, alkoxy, haloalkyl, cycloalkyl, phenyl, benzyl, and heteroaryl, by itself or as part of another group, is independently substituted with 0 to 3 R d ; and
R d is each independently halo, cyano, hydroxyl, amino, C 1-6 alkyl, C 3-6 cycloalkyl, or C 1-6 alkoxy.
21. A pharmaceutical composition comprising one or more compounds according to claim 1 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
22. A method of relieving the disease-state and/or reducing the risk of a disease, disorder, or condition selected from idiopathic pulmonary fibrosis (IPF), non-alcoholic steatohepatitis (NASH), non-alcoholic fatty liver disease (NAFLD), chronic kidney disease, diabetic kidney disease, and systemic sclerosis, in a patient having the disease, disorder, or condition, comprising administering a therapeutically effective amount of a compound or a stereoisomer, a tautomer, or a pharmaceutically acceptable salt or solvate thereof according to claim 1 .
23. A pharmaceutical composition comprising one or more compounds according to claim 12 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
24. A pharmaceutical composition comprising one or more compounds according to claim 13 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
25. A pharmaceutical composition comprising one or more compounds according to claim 14 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
26. A pharmaceutical composition comprising one or more compounds according to claim 15 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
27. A pharmaceutical composition comprising one or more compounds according to claim 16 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
28. A pharmaceutical composition comprising one or more compounds according to claim 17 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
29. A pharmaceutical composition comprising one or more compounds according to claim 18 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
30. A pharmaceutical composition comprising one or more compounds according to claim 19 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.
31. A pharmaceutical composition comprising one or more compounds according to claim 20 , or a stereoisomer, tautomer, or pharmaceutically acceptable salt or solvate thereof; and a pharmaceutically acceptable carrier or diluent.